Ep 101 Immortality: This Podcast Won't Kill You

had actually recorded before monkey pocks. So throughout this episode you may hear references to this being our one hundredth episode, even though it's actually episode one hundred and one, and we just wanted to explain why in advance. Okay, I think that about covers it, So let's get started introducing immortality. The life that you seek you never will find. When the gods created mankind death, they dispensed to mankind life

they kept for themselves. But you, Gilgamesh, Let your belly be full, enjoy yourself always by day and by night. Make mary each day, dance and play day and night. Let your clothes be clean, Let your head be washed. May you bathe in water. Gaze on the child who holds your hand. Let your wife enjoy your repeated embrace.

not aging, being invulnerable to any illness or injury. Does it mean that your name and life will be remembered hundreds of years from now, or that your genes will be carried on in your offspring and their offspring, and so on and so on down the line. There are many different ways that we can think of and have thought of immortality. And if your goal is to achieve immortality, which definition you choose has tremendous bearing on how you go about that, And that can also be said for

this episode. So how will we consider immortality today? Really, we'll at least touch on the most common concepts in a general sense, but since we're a health and science podcast, most of what we'll talk about is immortality from a biological perspective. First by talking about not what immortality is and how we can achieve it, but what stops us from being immortal in the first place? Why do we die? Why do we decline as we get older? Are there

any organisms that don't? What do we know or think about senescence, the decline or deterioration we experience as we age from an evolutionary perspective, And then all turn from that to talking about the age long quest for immortality, which has roots much much older than these startups in Silicon Valley that have been looking for modern elixirs of life that I know you're going to be talking a

bit more about, Aaron Yeap. What patterns do we see in the different ways that people have approached immortality through history? And how has this past century and our ever growing understanding of biology changed the targets for immortality research. And then that's sort of where I'll hands it off to you Erin to tell us how close we are or probably aren't to achieving immortality and the nitty gritty of what people are working on. Okay, okay, all right, so

let's get into it. Living things age, but they don't just experience the passage of time. They also change as time passes, first growing and developing, and then at a certain point that growth ceases and a new kind of change occurs, one where maybe things don't heal quite as fast as they used to, or those aches and pains get more frequent, and eventually recovery is no longer a possibility, with death being the ultimate end. And this is generally

how it happens for every living thing. And sure, the amount of time that you spend in each life stage may be different, or how long you can expect to live will vary, but death and aging are essential parts of life, even for those supposedly immortal animals that you see like click bait headlines about like lobsters or certain jellyfish or bristle cone pines. But while senescence, the biological decline part of aging may not be as marked as

in other creatures, those organisms are not truly immortal. They will die eventually because nothing living is immune to death. Why does this have to happen? Like, why can't we go on living forever? Well, let's think about it in the context of natural selection and evolutionary fitness.

or survive through reproductive age. Those traits lower your fitness and make it less likely for those genes to be passed on to the next generation. And over time those traits those genes will become less and less common, maybe eventually disappearing. But traits that make you more likely to reproduce or survive through the end of reproductive age, those are the traits that are going to be selected for

becoming more common. So we can think of tons of examples of this, right, like the size of a bird's beak, or the rate of development of a tadpole into a frog, or fur pattern or susceptibility to disease. But what's so crucial about this for this discussion is not the trait themselves, not these examples, but rather the time window when these traits matter most, and that is the critical period from basically prenatal development all the way through the end of

when you are able to reproduce. That is when selection can act. With this in mind, what does it matter really in terms of natural selection if you live past reproductive age. It doesn't.

So essentially, in terms of natural select it doesn't really matter how long we live past the point when we're no longer reproductively viable. And this is of course like a big oversimplification, and for humans and other animals, there are some very interesting hypotheses about why we humans live long past the age we reproduce, mostly centering around grandparents, and I'd love to get into that one day with an episode on menopause. Oh.

and other organisms age? Like? Why do we age? And we have been asking ourselves this question, probably since we were able to form thought, but it wasn't until Charles Darwin introduced the theory of evolution by natural selection in the mid nineteenth century that people had a scientific framework that they could use to try to answer this question. Since that time, many different hypotheses have been proposed, none of which seem to adequately explain sinessence for every living thing.

And I'm going to briefly go through a few of the classical hypotheses of sinessence so that we can try to think about possible mechanisms that could explain why aging

is universal. The first of these hypotheses was proposed in the eighteen nineties by the German evolutionary biologist August Weismann the so called germ soma theory, and so Weisman suggested that there were two types of cell lines in an organism, a germ line and a soma or body line, and the germ line is made up of the cells that are involved in reproduction and the soma line consists of the cells that make up the rest of the body.

It's the sole duty of the soma cells to do whatever it takes to keep the germ line alive and reproducing. Beyond that, soma cells basically disposable, and the soma cell lineage will invariably die, while the germ cell lineage can be viewed as potentially immortal. Aging happens as the soma line gets beat up by the environment while protecting the

germ line. And that's the hypothesis. Yeah, obviously it has many shortcomings, first of them being that it doesn't really explain why sinessence evolved, like why the soma is disposable,

and it doesn't explain sinessence in single celled organisms. But it did introduce the idea that reproduction is first and foremost the priority, and many later researchers built upon this idea, such as the famous mathematician and eugenicist Ronald Fisher, who in the nineteen thirties proposed a mathematical model in which he laid out his thoughts that sinessence was the accumulation

of harmful age specific traits. A couple of decades later, in the nineteen fifties, Peter Medowar, whose name you might remember from our organ transplantation episode. He wrote a now famous essay describing how the force of selection weakens as we get older and past our reproductive age. He wasn't entirely right either, For instance, his belief that animals in the wild don't get old they don't siness because they just get picked off by predators or succumb to starvation.

They actually do siness, they actually do get older. But his essay did suggest a sort of mechanism for Sinessence, if there are genes that do exist that shorten our lifespan, they won't really be selected against if they only show their effects later in life, and so they will continue to appear and accumulate over generations. The quote mutation accumulation theory.

you get larger faster and can be independent faster. But later on that could mean uncontrolled cell growth aka cancer.

It was, and it's still today is super impactful because it laid out a framework for why aging happens, and it also showed that the strength of selection on traits that keep you alive it becomes weaker over time in anything that ages and doesn't reproduce via fission. Yeah. Really, Also what it did was create a math model for people to be able to to test ideas about aging. The last of the classical hypotheses of sinessence I'm going

to talk about is the quote disposable soma theory. Proposed by Thomas Kirkwood in nineteen seventy seven, which says that over time and organism cells accumulate harmful genetic mutations. Mutations in your DNA happen randomly all the time because of environmental factors or mistakes in DNA replication, and it gets increasingly costly to repair the damage from these mutations, and at a certain point, the benefit of repairing the damage is outweighed by the cost repair and maintenance is always

going to favor the germline. Okay, so these are just a few of the most impactful hypotheses to explain why sinessence evolved, but there are certainly others, and no single hypothesis at this point seems to be able to explain aging for all organisms. There's no unifying hypothesis, probably because like there's tremendous diversity in life, no is there.

And the biggest thing in my eyes is that we've really only begun looking at this within the past one hundred and thirty years or so, which is shorter than the average lifespan of some organs. That could give us really valuable insight into longevity.

like it is, it is really hard to do it justice. Yeah, yeah, so yeah, So I just kind of wanted to like wander through some of these ideas and kind of fell and build a baseline for thinking about aging in an evolutionary context, especially when it comes to like natural selection and wouldn't it be great if we lived forever but we don't really need to, yeah, in terms of our DNA.

Immortality narratives are central to every culture and religion, like the Epic of Gilgamesh, the oldest known written document. So the reason that I included Gilgamesh in the beginning, I'm like now calling back to it is that a big part of the story is about the quest for immortality. So King Gilgamesh's best friend dies and in response, Gilgamesh vows to find eternal life. Spoilers he does not. And I'm sure between the two of us we can think of dozens and dozens more books or movies or poems

or songs about the search for eternal life. But it's not just like one of my favorite books growing up. Let's talk Everlasting and for a long time you have you read talk ever Lasting?

are more in line with this episode. While researching for this episode, I came across a book titled Immortality, The Quest to Live Forever and How It Drives Civilization. And in this book, the author philosopher Stephen Cave, groups the search for immortality into four different themes. The first two deal with the physical side of things. First, there's living forever, you as an individual, stopping aging or aging but not dying,

living indefinitely. And then there's resurrection, being brought back to life after death, think Jesus. Third is the soul, the idea that a part of you, but not the physical you lives on after you die. And finally, there's legacy, which can mean living on through memories or fame, as in your only truly dead when your name is no longer said Coco, or also offspring the idea that your

genes achieve immortality by being passed on. And I wanted to explore some of the ways we've sought to achieve immortality throughout human history, focusing on those that fall into the first two of these themes, staying alive and resurrection, because in terms of targets for biological research into immortality, all of those projects can be lumped into those themes. Yeah, And after going through some of these adventures and immortality, I want to end by reflecting on what these stories

tell us about human nature. Here. Humans may be unique in our ability to recognize our own mortality that one day, each and every one of us will die, and the knowledge of our own inevitable death, Yet the simultaneous inability to actually imagine what it will be like has driven us to find any way around it, either by delaying it,

undoing it, or preventing it entirely. In ancient Egypt, there was an entire industry devoted to preserving the body after death so it could be magically revived, and of course, pyramids and other monuments were built as a testament to the person's life immortality through legacy. Ancient papyri describe not just preparation for the afterlife or resurrection, but also ointments and elixirs that were meant to extend life and slow aging. The search for an elixir of life or a fountain

of youth is similarly old. There are countless stories of emperors and kings searching in vain for a way to escape death, like the first Emperor of China, who lived around the two hundreds BCE. He became obsessed with the idea of living forever and searched high and low for someone who could reveal the secret to him. He did find someone, probably one of the oldest known swindlers, who promised it all but delivered nothing and just ran away

with his reward. Of course, ultimately the emperor died young, only forty nine, likely from either arsenic or lead or mercury poisoning, all of which were likely ingredients in his daily life. Extending vitamins.

a cure all for any disease. It was practiced all over the world from ancient times all the way up through the eighteenth century, when it declined after the rise of more rigorous scientific thinking, although it might be more accurate to say that alchemy didn't decline, but rather it was repackaged primarily into the field of chemistry. Nor did people grow tired of looking for the elae of immortality. Instead, the development of each new field or new scientific discovery

was applied to that quest, For instance, electricity. So if you think back to our electricity episode, you may remember me telling the story of Galvani and his metal wires and the frog's legs jumping. So his nephew took a page out of his book and held public demonstrations where he reanimated corpses of freshly hanged murderers.

became our targets for modern day immortality projects. And the amazing thing in my eyes is that despite humanity's continuous and innumerable attempts to achieve immortality, over thousands and thousands of years, we have not been remotely successful, and we probably never will be. Maybe it'll change my mind.

not been an extension of our inherent life span. Humans have been able to live to eighty years old ninety years old for thousands of years, but were prevented from commonly achieving old age because of extrinsic factors like insert any vaccine preventable disease here.

Some of these projects have uncovered knowledge that has had huge implications, who are improving quality of life and treating diseases that primarily manifest later in life. I guess I'm just expressing my skepticism that a meaningful extension of both lifespan and quality of life alongside that will be achieved in the near or even kind of near future. The section definitely came out differently than I had planned when

I started it. I thought I'd take us through the history of the search for the elixir of life or the beginnings of cryonics, and those stories are fascinating and worth telling. But I think that overwhelmingly while doing the research for this part, and while going through it just now, I think that what sticks out to me most is

how so many things have not changed. We will continue to keep looking for ways to live forever, to upload our brains or slow our aging, to reanimate form and bodies, or download our memories into a cloned body, and if any of those technologies are successful, you can also be sure that the select few, the richest, and most powerful will be the only ones to benefit from them, which is also how it has been throughout history. But would it truly be a benefit to live forever? Would it

be something you want? I've talked about a few stories about people who have searched for a way to live forever. Now let's think of some where they achieved immortality. How did those stories end?

considering what that could truly look like. I want to end this section with a quote by Stephen Cave that I think puts it nicely. Quote The deep problem is this, The value of a thing is related to its scarcity. People conscious of their mortality value their time and aim to spend it wisely because they know their days are numbered. But if our days were not numbered, this incentive would disappear.

Given infinity, time would lose its worth, and once time is worthless it becomes impossible to make rational decisions about how to spend it. The consequences of this for an individual would be bad enough. For a civilization of such ditherers, it would be disastrous.

stand today? So what was my question for immortality? Is it? How close are we to immortality? Is it? Are we still pursuing this quest? Which spoilers you already told us And the answer is yes, we still are. Oh was the question have we learned anything from these thousands of years of futility so far? I don't know what question

I'm answering out of those. But I did a lot of reading, and I read a lot about the various you know, Silicon Valley startups that exist, the number of companies, the number of billionaires and millionaires, and the amount of dollars that are going in to try to solve this quote problem of aging or the problem of death.

talking about increasing our lifespan. And if we're talking about halting aging to the point of halting death, then for me, the way to get there, logically is to answer a series of four different questions. The first question you kind of answered, Aaron, and that is why do we age? I think that you provided a lot of evolutionary perspective on the idea of why we as humans and we as living organisms on the planet Earth age evolutionarily, but we still don't fully necessarily know. We at least have

a lot of hypotheses. But a very closely related question to why do we age is how do we age? Like fundamentally, what governs the process of how our selves siness? And how is this process related to those evolutionary reasons of why we age? Because if we could answer those two questions really well, then we could ask the next question, must we age? Are those processes, like we said, from an evolutionary perspective, necessary for life? And are they immutable?

And if the answer to that question is no, they're not immutable. And if we can figure that out by virtue of figuring out the answers to the first two questions, then we can ask the final question, if we don't have to age, do we have to die? So, at least to me, those seem like the four fundamental questions that have to be answered if we have any hope

of answering this riddle of immortality. And suffice to say, those four questions are massive, and I think the biggest issue for me in talking specifically about immortality is the leap between those last two questions, must we age and must we die? Right? Because while there are in nature and in the laboratory many many examples be they plant or worm or lobster that live a very long time that seem to be immortal, nothing is invincible, right, right.

If you take one of these invincible planarians out of their worm juices, they're going to die. They're not invincible. And so that's I think one of the biggest issues I see with even just entertaining this idea of true immortality.

especially how we age and must we age? There has been like you said, Aaron, without a doubt huge increases in the estimated life expectancy for humans globally, and there is a lot of variation in estimated life expectancy between countries, between genders, et cetera. And most of that increase is,

like you mentioned, credited to early life advancements, things like antibiotics, vaccines. Basically, we know for sure that we've had huge reductions in early life mortality because of scientific and biomedical achievements over the last fifty twoe hundred years. However, there has also

been a decline in late life mortality. So the fraction of each birth cohort that reaches old age has been increasing year after year, or at least it had been until about the nineteen eighties, and since then it's actually been very stagnant despite increasing overall life expectancy, but the maximum reported age at death has plateaued. You may have heard of Jean Calmeat, who was a French woman who died in nineteen ninety seven at the ripe age of

one hundred, twenty two years and five months. She still holds the verified longevity record by a lot, by a couple of years. And while there are over five hundred thousand centenarians alive worldwide, at least that's what the UN estimated in twenty twenty wow, five hundred thousand people over one hundred. That number is twenty times higher than fifty years prior. But the average age at death for these

centenarians has not increased since nineteen sixty eight. So there is a lot of research and mathematical modeling like you mentioned erin as far back as the eighteen hundreds, that really suggest that there may be a true upper limit to the human life span. And while this idea is still a little bit controversial, there are people who don't like to agree with the idea that there is a

limit to human life expectancy. A lot of studies that have used various methods and are to varying degrees controversial, have converged around this idea that perhaps between one hundred and twenty and one hundred and fifty years might be the maximum human lifespan that one could expect. So could we even live forever? It seems highly unlikely. Yeah, But there is another piece to this puzzle besides actual lifespan is, like you mentioned Aaron, quality of life. This is often

called health span. So if life span is the length of your life. Health Span is often defined as the period of your life that is free from disease. I personally will take slight issue with this definition, because health is of course a lot more than merely the absence of disease, but this is generally how health span is defined,

so we'll go with it for the purposes of this episode. Okay, And if we look worldwide, despite how much lifespan has increased, chronic diseases are the leading cause of morbidity and mortality worldwide, and many of these cardiovascular disease, cancer, dementia. These are often considered diseases of aging, and an estimated fifty eight percent of chronic disease related mortality happens in people over

age seventy. So if we look at the discrepancy between health span and lifespan, there's an estimated gap right now in the world of nine years. So there's a nine year gap where you are still alive, but you are no longer quote free from disease. And a lot of the field of what is called gerontology research isn't truly focused on the idea of immortality, at least not overtly or in a lot of cases, they're not even focused on the idea of increasing our lifespan, but rather they're

focused on increasing health span. So they talk instead about the idea of compressing our morbidity to the end of life, such that we live healthier lives for longer and can either avoid or prolong the onset of these various age related diseases. And this I think sits as both a more palatable goal. For sure, I would agree with that, but I also think that it's closer to what seems maybe yes, although I do stress that we're not there yet.

on these mechanisms. But we can define, based on what we know so far, about nine different flavors or nine different targets that are related to aging and potentially modifiable at least in cell culture and or in animal models, or maybe just theoretically modifiable. So I'll mention all of these, but spoiler alert. Reading some of the papers that go into detail on this, I had a very difficult time

following through. But let's at least look at what we know about aging, because it turns out we know a lot more than you might think. So when we look at the mechanisms of aging, one of them Aaron you mentioned already, and that is damage to our DNA be that nuclear DNA or mitochondrial DNA. Basically, over time, insults to our bodies result in the inability of our bodies to properly repair damage to our DNA the way that

it is supposed to. And there are a lot of different potential genes involved in this and specific mechanisms that researchers have altered in flies or in worms, or just in cells. But essentially this genomic instability does play a really big part in the process of aging. So if there was a way to make our DNA more easily able to repair itself, that could then delay that process of aging, and we know delay a lot of the age related diseases that are related to this, like cancers,

like maybe heart disease. There's also telomere damage telomere's I think we talked about in our HPV episode. Was that right?

regenerative capacity of tissues and therefore accelerated aging. So in mice models and in other animal studies, telomere length has been shown to be associated with lifespan in humans. It's not quite that simple, but this is at least another potential target.

into epigenetic modifications. Epigenetics we've only ever briefly mentioned, but I actually think I talked a bit about it in our full late episode. It's kind of fun.

Any of these changes are considered part of epigenetics, and changes in a number of different things from methylation to histone proteins have been shown to be associated with aging. There is a family of enzymes called sirtuins I think that's how you pronounce it, that are involved in DNA methylation and got a lot of press because in yeast and in worms, when these enzymes are manipulated, then you

can increase lifespan by significant in a worm. Again in humans, we don't have any data to show that as of yet, but that's at least the idea that epigenetics likely plays a big role in the process of aging. So if this is something that we could target, we could maybe affect it. Yet another target would be proteastasis, so Basically, our cells are both DNA and proteins, right, So as we age, our cells become less able to maintain proteins

in the correct stable configurations and correct functionality. If you think of something like Alzheimer's disease, this is largely a disease of protein misfolding. So there are a lot of studies in cells in yeast, and I think at least some in worms and flies that if you mess with some of the genes related to protein stability, then you

can precipitate aging make them age faster. So that suggests that these systems are directly involved in the process of aging, and thus if they could be manipulated in the opposite way, could perhaps promote longevity or reverse aging.

have not enough food. And this goes along with a lot of data in mice and in some primates of caloric restriction. So having less food for a portion of your life increases lifespan in a lot of animal models. So there are a lot of different host factors that are implicated as a possibility in this. Some of them are things you've definitely heard of, like insulin right or

IGF one insulin growth factor one. There are a lot of others like m tour amp K sirtuins are in amp K. These are all various fancy names for factors that our body uses to help signal to our brain when there is food that needs to be digested versus when our nutrients stash is very low, so we need to engage in catabolism like break down our own stores

instead of building a bunch of muscle in fat. So there's evidence to suggest that states of anabolic signaling that is our body saying, hey, we've got a lot of food, we need to build up stores. That process accelerates aging, at least in mice and so manipulating this signaling so that a mouse's metabolism thinks it's living underlimited nutrients. By manipulating some of these factors can extend longevity.

for human beings. This could be very dangerous, okay, but in mice, restricting them to that very small amount of calories thirty to forty percent of what would normally be needed, does increase lifespan, and it also increases the age at which animals are able to reproduce, if that makes sense.

building fat, and that might make us live longer. That's the theoretical idea behind it.

at least from what I read. And apologies. If someone has some great data that I didn't see on these last few.

likely to the process of aging. Okay, there's also just the idea of cellular sinescence in general, cells going quiescent over time. A lot of our cells in our body are not dead, but they no longer divide, they're no

longer active. So there's a large thought that just this entire process of cells kind of turning off a lot of their activity then relates to aging, and it's likely protective to write, like, reduce the amount of DNA damage that might occur through the process of replicating cells that don't need to be replicated, et cetera. So this might be something that's more related to protection against aging rather than involved in the process of aging, like protective against it.

But there's also a lot of other ways that our cells communicate with each other besides potentially a bioelectric field. But I will link to that Ted talk because it's fascinating and it's likely that this process over time also becomes defective and is involved in the process of aging. That was like a very fast speed through and I

know that I left a lot of detail out. I will cite a couple of papers, one from twenty thirteen that's a few years old now, but another that is a summary of a twenty twenty one symposium of gerontologists that has a lot more detail on these nine different processes and where we kind of stand in terms of in vitro cell data, animal model data, and human data.

But the thing is, I think it's very clear just for going over all those various processes that these are all very interconnected, right, especially when we talk about humans. It's not one single piece. All of these processes are likely at play, and we are not at a point where we can say that we have an answer or a drug or an intervention at all. That can prolong our life in any meaningful way. We don't even have one that could likely prolong our health, at least not yet.

So really, for me, what it comes down to is that forever it is a very very long time. So do I think it's possible that humans will ever unlock the many locks between us and immortality? No, I will say, no, Yeah, it doesn't seem likely. It doesn't. Do I think that it could be theoretically possible this concept of immortality kind I kind of don't, Aron, do you know?

various age related diseases, cardiovascular disease, cancer, Alzheimer's disease. We study these diseases in isolation.

diabetes itself and cancer itself. Let's think about these things that underpin both of those or all of those. And so I think that that's kind of the argument of a lot of the people who do this type of research, and I think it's really valid. And maybe that's the gap that some of these biotech companies are filling by directing their funding to address that. I don't know, maybe that's an optimistic view, but maybe that is.

Because the increase in life span that we've seen in the last fifty to one hundred years hasn't been even across the board, and people who are wealthy live much longer than people who are not wealthy, and so that is likely going to continue to be true, especially if all of the research being done on this is from a capitalistic perspective of companies trying to make money off of it.

and that's from twenty seventeen. And then the book that I already mentioned by Stephen Cave Immortality the Quest to Live Forever and how it drives Civilization, and those are both really I just really enjoyed the Stephen Cave book as an interesting way to look at immortality.

Span Gap. And then there was there's a bunch more so I'll link to them on our website, This podcast will kill You dot com under the episodes TAT.